Dialyzers for blood treatment and processes for production thereof

ABSTRACT

A dialyzer for blood treatment including a semipermeable membrane which is made of a hydrophobic polymer and a hydrophilic polymer, and has a water permeating performance drying of ½ or higher relative to that before drying. The dialyzer has a vitamin B12 clearance not smaller than 135 ml/mm per 1.6 m 2  or the amount of the hydrophilic polymer eluted from the semipermeable membrane is not higher than 10 ppm. A dialyzer for blood treatment is light-weight, easy to handle, and exhibits a reduced elution of the hydrophilic polymer procedures for producing a dialyzer containing the semipermeable membrane and a process for producing a hollow fiber membrane for use in blood treatment are described.

This application is a divisional of application Ser. No. 09/736,373filed Dec. 15, 2000 now U.S. Pat. No. 6,605,218, the entire content ofwhich is hereby incorporated by reference in this application.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a semipermeable membrane for bloodtreatment which exhibits little change in performance upon drying andreduced elution of a hydrophilic polymer therefrom; a dialyzer for usein blood treatment using the same; and a processes for producing adialyzer having incorporated therein a semipermeable membrane whichexhibits little change in performance before and after drying andreduced elution of a hydrophilic polymer therefrom.

2. Description of the Related Art

As a material for a semipermeable membrane for blood treatment such asan artificial kidney, there have been used a number of materials. Forexample, a natural material cellulose and its derivatives, e.g.,cellulose diacetate and cellulose triacetate, were originally used, andsynthetic polymers were then developed, such as polysulfone, polymethylmethacrylate (PMMA) and polyacrylonitrile. Recently, modified cellulosemembranes have also been used which is prepared by treating cellulosewith polyethylene glycol (PEG) or the like to modify the compatibilityto blood. In semipermeable membranes for blood treatment in patientssuffering from chronic renal failure, attempts have been made to reducethe leakage of albumin to a minimum while positively removing lowmolecular proteins other than albumin. In addition to such improvementin the membranes, hemodiafiltration (HDF) procedures and push-and-pullprocedures have been developed for increasing the dialysis efficiencyand positive removal of undesirable low molecular proteins. Polysulfone,which has a high water permeability, is now widely used since it meetsthe above-mentioned requirements. In a polysulfone membrane, ahydrophilic polymer is generally blended to impart an affinity for bloodto the membrane. However, the polysulfone membrane has such a defectthat once it is dried the properties tend to be changed to a greatextent. Hence, it is difficult to produce a dry type of polysulfonemembrane dialyzer which is light-weight and easy to handle.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide adialyzer using a dry or semi-dry type of semipermeable membrane whichhas advantages such as light-weight and resistance to freeze, whereinthe semipermeable membrane is improved in water permeability and dialyzeperformance (which are poor in a conventional one) to the same level asthose of a wet type one.

It is another object of the present invention to provide a dry orsemi-dry type of dialyzer having advantages such as light-weight andresistance to freeze, wherein the dialyzer is improved in waterpermeability and dialyze performance (which are poor in a conventionalone) to the same level as those of a wet-type one and exhibits a reducedelution of a hydrophilic polymer therefrom.

That is, in an aspect of the present invention, there is provided adialyzer for blood treatment having incorporated therein a semipermeablemembrane which comprises a hydrophobic polymer and a hydrophilicpolymer, the water permeating performance of the semipermeable membraneafter drying being ½ or higher relative to that before drying and thedialyzer satisfying any of the following requirements:

(A) the vitamin B12 clearance is not smaller than 135 ml/min per 1.6 m²;and

(B) the amount of the hydrophilic polymer that is eluted from thesemipermeable membrane is not higher than 10 ppm.

In another aspect of the present invention, there is provided a processfor producing a dialyzer having incorporated therein a semipermeablemembrane which comprises a hydrophobic polymer and a hydrophilicpolymer, the process comprising:

drying the semipermeable membrane; and

saturating the dried semipermeable membrane with water ratio of notsmaller than 100% based on the dry weight of the semipermeable membrane,providing an inert gas atmosphere to the inside of the dialyzer, andthen irradiating the semipermeable membrane with gamma-ray in the inertgas atmosphere.

In still another aspect of the present invention, there is provided aprocess for producing a hollow fiber membrane for use in blood treatmentthrough dry/wet spinning from a spinning solution comprising 15 to 18%by weight of a hydrophobic polymer and 4 to 8% by weight of ahydrophilic polymer, the dry zone being filled with dry mist.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, the hydrophobic polymer to be used in thesemipermeable membrane includes a number of engineering plastics, suchas polysulfone, polyamide, polyimide, polyphenyl ether and polyphenylenesulfide. Preferably, the hydrophobic polymer is polysulfone representedby the formula below, which shows the skeleton of the polysulfone.Polysulfone derivatives in which the benzene ring in the skeleton ismodified are also usable in the present invention.

The hydrophilic polymer to be used in the semipermeable membraneincludes, for example, polyethylene glycol, polyvinyl alcohol,carboxymethyl cellulose and polyvinyl pyrrolidone, which may be usedalone or in combination. Polyvinyl pyrrolidone (hereinafter, sometimesreferred to as “PVP”) is preferred since it is relatively high inindustrial availability. It is preferable to use two or more ofhydrophilic polymers having different molecular weights. In thisinstance, the hydrophilic polymers preferably have different weightaverage molecular weights from one another by five times or more.

The spinning solution to be used for the preparation of thesemipermeable membrane preferably comprises a hydrophobic polymer, ahydrophilic polymer, a solvent and an additive. The solvent may be anamphiprotic solvent which can fully dissolve all of the hydrophobicpolymer, the hydrophilic polymer and the additive. Specific examples ofthe solvent include dimethylacetamide, dimethylformamide,dimethylsulfoxide, acetone, acetaldehyde and 2-methyl pyrrolidone.Dimethylacetamide is particularly preferred from the viewpoints ofsafety, stability and toxicity. The additive may be one which is a poorsolvent for the hydrophobic polymer but is miscible with the hydrophilicpolymer, such as an alcohol, glycerin, water and an ester. Water isparticularly preferred from the viewpoint of process suitability.

The viscosity of the spinning solution for membrane production maydepend on the molecular weight of the hydrophilic polymer, sincecommercially available hydrophilic polymers have low molecular weights.A decreased viscosity of the spinning solution could cause breakage orswinging of fibers during the preparation of a hollow fiber membrane,leading to a decreased stability of the resulting hollow fiber membrane.Accordingly, when PVP is used as the hydrophilic polymer, PVP with ahigh molecular weight is preferred. When two or more types of PVP areused in a mixture, the PVP mixture preferably has an average molecularweight of 200,000 or higher.

Next, the contents of the hydrophobic and hydrophilic polymers in thespinning solution is described. As stated above, as the polymer contentincreases, a membrane can be formed more effectively but the porosity ofthe resulting membrane decreases, leading to a decreased waterpermeability. Accordingly, there is an optimum range for the polymercontent. To obtain a membrane that can exert both a high permselectivityand a low albumin permeability even when dried, like one produced in thepresent invention, the concentration of the hydrophobic polymer ispreferably 10 to 20% by weight, more preferably 12 to 18% by weight, andthe concentration of the hydrophilic polymer is preferably 2 to 20% byweight, more preferably 3 to 15% by weight. In the case where two ormore hydrophilic polymers having different molecular weights are used,it is preferable that the content of hydrophilic polymers havingmolecular weights of 100,000 or higher in the spinning solution is 1 to10% by weight. If this content is too large, the viscosity of thespinning solution increases, which may cause difficulty in formation ofa membrane, as well as decrease in water permeability and diffusionperformance. On the contrary, if this content is too small, it becomesimpossible to construct a desirable network structure desired for thepermeation of medium-to-high molecular weight uremia-toxic proteins.

When the hydrophilic polymer is a polysulfonic resin and the hydrophilicpolymer is polyvinyl pyrrolidone, preferably the polyvinyl pyrrolidonein the semipermeable membrane is 1 to 10% by weight based on the contentof the polysulfonic resin.

An embodiment of the process for preparing the semipermeable membrane isdescribed hereinbelow. A spinning solution having a composition asmentioned above, along with a core solution, is extruded from aspinneret through an annular double slit tube to form a hollow fibermembrane. The membrane is washed with water, dried, and then crimped.The crimped membrane is taken up and cut to an appropriate length. Thecut membranes are placed in a module case, in which both end faces ofthe bundle of the membranes are sealed with a potting material. In thismanner, a hollow fiber membrane module is produced

Preferably, the membrane is formed by a dry/wet spinning process, inwhich a dry zone is filled with dry mist. The dry mist refers to amist-like material comprising water particles of 10 μm or smaller. Theintroduction of the dry mist into the dry zone can generate cores whichmay play an important role in the process for forming an outer surfaceof the hollow fiber membrane. PVP can coagulate around the cores to formPVP phases; thus, phase separation occurs in the dry zone. Subsequently,the fully grown PVP phases are removed in the coagulation bath,generating large pores. A conventional polysulfone dialyzing membranegenerally has an asymmetric structure, where the permeation of materialis controlled only through the inner surface. However, by providing suchlarge pores on the outer surface of the membrane, an outer support layerhaving a coarse, porous structure can be formed. This structure enablesa substance to be transferred through the membrane by diffusion morereadily, thus providing an increased permeation performance to thefinished dialyzing membrane.

In the present invention, for the formation of the hollow fiber membrane(not “module”), a conventional process including the treatment of thehollow fiber membrane with a moisture-retaining agent but not includingany drying of the membrane is not employed and, instead, a processincluding the positive drying of the membrane is employed. As a result,a hollow fiber membrane of which water permeating performance afterdrying is ½ or higher relative to that before drying can be produced.Preferably, it should be 75% or higher, and more preferably it should be90% or higher. In the process of the present invention, since themembrane is dried without the treatment with a moisture-retaining gent,the spinning solution should be designed taking the shrinking of thedried membrane in consideration. When the semipermeable membrane is usedin this state particularly in an artificial kidney, however, aconsiderable amount of the hydrophilic polymer may diffuse from themembrane. For the purpose of reducing such elution, it is preferablethat the membrane be subjected to a cross-linking treatment withgamma-ray irradiation, electron beam irradiation, or heat or chemicaltreatment. If gamma-ray is irradiated in the presence of air (i.e.,oxygen), the breakage of the backbone of the hydrophilic polymer couldoccur by the action of excited oxygen radicals, resulting in thedecomposition of the polymer. To solve this problem, it is preferable tosaturate the membrane with water ratio of not smaller than 100% and nothigher than 1000%, more preferably 100 to 600%, still more preferably100 to 400% based on the dry weight of the membrane, replace theatmospheric air with an inert gas, and then irradiate the membrane withgamma-ray. Thus, elution of the hydrophilic polymer from the membranecan be prevented effectively. As the inert gas, nitrogen, argon, heliumand carbon dioxide are preferably used. Nitrogen, which is inexpensive,is particularly preferred. The exposure dose of gamma-ray is preferably10 to 50 KGy, more preferably 10 to 30 KGy. Since the cross-linkingtreatment induces the binding between the hydrophobic polymer and thehydrophilic polymer, elution of the hydrophilic polymer from themembrane can be reduced. The forced elution test of the membrane asdescribed below demonstrated that any peak indicating the presence ofthe hydrophilic polymer eluted from the membrane was not observed.Accordingly, a semipermeable membrane having an elution amount of nothigher than 10 ppm can be manufactured. The term “an elution amount”refers to the amount of the hydrophilic polymer in an extract that isprepared by dispersing or dissolving a certain amount of hollow fibersinto a solvent which is a good solvent for both the hydrophobic and thehydrophilic polymers, has a solubility against the both polymers of notsmaller than 0.5 g/ml and is immiscible with water, and then extractingthe hydrophilic polymer from the solution with a certain amount ofaqueous phase (0.1N ammonium chloride solution, pH 9.5) to give theextract. In the case where the hydrophilic polymer is a mixture ofpolysulfone and polyvinyl pyrrolidone, the good solvent is preferablymethylene chloride.

The semipermeable membrane prepared as mentioned abovecharacteristically exhibits good performance as a membrane for bloodtreatment, such as good diffusing capacity for uremia-causing substancesand diffusion resistance against a useful protein albumin, and has areduced elution of the hydrophilic polymer therefrom, due to the networkstructure formed with the hydrophobic and hydrophilic polymers. If thealbumin permeability exceeds 3%, physical conditions of hypoalbuminemiapatients or the nutritive conditions of elderly persons may affected.Therefore, the albumin permeability is preferably 3% or lower. Theuremia-causing substance or uremic toxin may be urea, creatinine or uricacid. As the indicator of the substance permeation, vitamin B12 may bementioned. In the semipermeable membrane of the present invention, thevitamin B12 clearance can be 135 ml/min or higher per 1.6 m². Theclearance of urea, creatinine and uric acid is preferably 188, 175 and165 ml/min, respectively, or higher per 1.6 m² in the practicalviewpoint.

In order to achieve the above-stated properties, the content of thehydrophilic polymer in the membrane after the cross-linking should be 1to 10%, and is preferably 2 to 6% by weight. Too small content may causereduction in wetting ability against water and coagulation may occurupon contacting with blood. It is also preferable that the membraneafter the cross-linking contain insoluble substances in a concentrationof 5 to 15% by weight.

A stated above, the semipermeable membrane for blood treatment accordingto the present invention can exhibit a water permeability after dryingof ½ or higher relative to that before drying, by employing a step ofdrying the membrane in the state where no moisture-retaining agent isattached to the membrane and a step of cross-linking the dried membraneafter moisture conditioning (i.e., saturating with water). As a result,the membrane can be applied to a dialyzer which exhibits good propertiessuch as decreased water permeability and less leaking of substanceseluted from the membrane even when used after drying. The membrane ofthe present invention can be used in a dry or semi-dry state (as usedherein, the term “semi-dry state” refers to a state where water iscontained in the membrane but spaces between the hollow fibers arefilled with a gas). Accordingly, a semipermeable membrane can beprovided which is light-weight, almost free from the problem of freezeand easy to handle and has excellent performance. The production of sucha semipermeable membrane may contribute to the reduced cost of thedialysis. Moreover, the membrane can exhibits a high dialyze performanceat various temperatures and sterilization conditions since degradationin dialyze performance hardly occurs by drying. On the other hand, inthe application to the treatment of a human body, elution of thehydrophilic polymer (a foreign substance to the body) can be reduced,leading to increased safety of the membrane as medical equipment. Thedialyzer according to the present invention is applicable to medicalapparatuses for blood treatment, such as an artificial kidney, a plasmaseparative membrane and a carrier for extracorporeal circulationadsorptive separation.

EXAMPLES

The invention will be described in more detail with reference to theworking examples below. The determination methods employed are asfollows.

-   (1) Determination of Water Permeability

A hydraulic pressure of 100 mmHg is applied to the inside of each hollowfiber in a glass tube mini-module (comprising 36 of hollow fibers;effective length—10 cm) in which both ends of the hollow fiber bundleare sealed), and then the amount of the permeate coming out of themini-module per unit time period is measured.

The water permeation performance is calculated in accordance with thefollowing equation:${{UFR}\quad\left( {{{{ml}/{hr}}/m^{2}}/{mmHg}} \right)} = \frac{Q_{w}}{P \times T \times A}$wherein Qw is the amount of the permeate (ml); T is the efflux time(hr); P is the pressure (mmHg); and A is the area of the membrane (m²)(in terms of the are of the inner surface of the hollow fiber).

-   (2) Determination of Change in Performance Upon Drying

When no moisture-retaining agent is attached onto a hollow fiber to betested, the fibers may be dried under the conditions below. However,when any moisture-retaining agent is attached, 10 g of the hollow fiberis soaked in 150 ml of pure water and allowed to stand for 24 hours.This procedure is repeated twice and then dried in the form of a fiberbundle at 100° C. for 24 hours. The water permeability is determinedbefore and after the drying.

-   (3) Determination of Clearance of Solutes

This determination is performed in accordance with the description of“the Performance Evaluation Criteria for Dialyzers” (the JapaneseSociety of Artificial Organs, ed., issued on September, 1982). In thispublication, there are shown two determination methods for clearance. Inthis example, the clearance is determined in accordance with the TMP 0mmHg value. Among the solutes tested, vitamin B12 may be decomposed byirradiation with light. Accordingly, it is preferred to determine theclearance of vitamin B12 within the day of sampling, preferablyimmediately after the sampling. The clearance is determined using theequation below. When the areas of the membranes used for this test aredifferent, the overall mass transfer coefficiency may be calculatedbased on the clearance value of each solute and the calculated value maybe converted in area terms.

Clearance:${C_{L}\left( {{ml}/\min} \right)} = {\frac{{CBi} - {CBo}}{CBi} \cdot Q_{B}}$wherein CB_(i) is the concentration at the module inlet; CB₀ is theconcentration at the module outlet; and QB is the rate of liquid fed tothe module (200 ml/min). QD (dialysate flow rate) is fixed to 500ml/min.

-   (4) Determination of Albumin Permeability

Bovine blood (treated with heparin) with a hematocrit value of 30% and atotal protein content of 6.5 g/dl, which has been kept at a temperatureof 37° C.), in a blood tank is used. The bovine blood is fed to theinside of the hollow fibers through a pump at a rate of 200 ml/min.During this process, the pressure at the module outlet is adjusted toachieve a filtration rate of 20 ml/min per m² of the module area (whichis equivalent to 32 ml/min per 1.6 m²), and the filtrate and the bloodfrom the outlet are fed back to the blood tank. One hour after the startof reflux, the blood at the inlet and the outlet of the module and thefiltrate are sampled. The blood samples are centrifuged to separate theserum. The serum is analyzed using the BCG (bromcresol green) method kitof A/G B-Test Wako (a tradename, Wako Pure Chemical Industries, Ltd.),and the albumin permeability (%) of the individual samples is calculatedfrom the serum concentrations. For the determination of albuminconcentration in the filtrate at high sensitivity, a calibration curvefor albumin at low concentrations is established by making appropriatedilutions of serum albumin included in the kit.${{Albumin}\quad{permeability}\quad(\%)} = {\frac{2 \times C_{F}}{\left( {{CBi} + {CBo}} \right)} \times 100}$wherein C_(F), CB_(i) and CB₀ are concentrations of albumin in thefiltrate, at the module inlet and at the module outlet, respectively.

-   (5) Determination of Concentration of a Hydrophilic Polymer PVP    Transferred into the Aqueous Layer in Forced Elution Test

One liter of pure water is passed through the dialyzing module from theblood side to the dialyzate side to wash the module. 1 g of the hollowfiber from the module is dissolved in 10 ml of methylene chloride (10%w/v). The solution is extracted with 10 ml of 0.1N ammonium chloridesolution (pH 9.5), and the resulting methylene chloride aqueous solutionis supercentrifuted (20,000 rpm×15 min). The aqueous layer is passedthrough a filter (pore size: 0.5 μm) to obtain a sample solution.

Analysis of the sample solution is performed at 23° C. using twoserially connected Toso TSK-gel-GMPWXL columns with a theoretical numberof steps (8,900×2) under the following conditions: mobile phase—0.1Nammonium chloride solution (pH 9.5); flow rate—1.0 ml/min; sampleloading—0.2 ml. Nine monodisperse polyethylene glycol products are usedas the standard materials for calibration of molecular weight and a peakarea-concentration calibration curve for a reference PVP product isestablished. The concentration of PVP transferred into the aqueous layer(5 ml) is determined from the PVP peak area of each sample solution.Samples containing a detectable amount of PVP are determined on therecovery of PVP (i.e., transfer rate into the aqueous layer) from thatof the reference, and the amount of PVP eluted into the aqueous layer iscalculated from the PVP concentration in the aqueous layer based on therecovery.

-   (6) Determination of PVP Content by Elemental Analysis

A sample irradiated with gamma-ray is dried at ordinary temperatureusing a vacuum pump. 10 mg of the dried sample is analyzed using a CHNelemental analyzer. The PVP content is calculated from the nitrogencontent.

-   (7) Determination of Insoluble Material Content

10 g of a hollow fiber irradiated with gamma-ray is dissolved in 100 mlof dimethylformamide. The solution is centrifuged at 1,500 rpm for 10min to separate insoluble materials, and the supernatant is discarded.This procedure is repeated three times. The insoluble material is washedwith 100 ml of pure water, and then centrifuged three times as mentionedabove. The resulting solid material is evaporated to dryness and thendried with a vacuum pump. The weight of the dried solid material is usedto calculate the content of the insoluble materials.

Example 1

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts of polysulfone(Amoco, Udel-P1700), 4 parts of polyvinyl pyrrolidone (InternationalSpecial Products, hereinafter, referred to as “ISP”; K30) and 2 parts ofpolyvinyl pyrrolidone (ISP, K90) were dissolved in 77 parts ofdimethylacetamide and 1 part of water with heating, to obtain a spinningsolution for membrane formation.

The viscosity of the spinning solution was 13.4 Pa·s at 50° C. Thespinning solution was introduced to a spinneret at 50° C., and extruded,along with a core solution comprising 65 parts of dimethylacetamide and35 parts of water, from the spinneret through an annular double slittube having an outside diameter of 0.35 mm and an inside diameter of0.25 mm, whereby a hollow fiber membrane was formed. The membrane wassubjected to moisture conditioning at 30° C. and a dew point of 28° C.The conditioned membrane was passed through a dry zone atmosphere whichhad a length of 250 mm and contained dry mist of 10 μm or smaller, thenthrough a coagulation bath at 40° C. comprising 20 wt % ofdimethylacetamide and 80 wt % of water. The resulting membrane wassubjected to a washing step with water at 80° C. for 60 sec, a dryingprocess at 135° C. for 2 min, and then a crimping step at 160° C. Theresulting membrane was taken up into a bundle. The hollow fiber membranebundle was packaged in a module case so that the area of the hollowfiber membrane became 1.6 m², and potted. The potted bundle was providedwith opening faces at the both ends to form a dialyzing module.Thereafter, blood side was filled with deaerated warmed water (37° C.)at a feed rate of 200 ml/min for 1 min and, then, an inert gas(nitrogen) was fed to the module at a pressure of 0.1 MPa for 15 sec toforce out the filling water therefrom. In this state, the water contentin the hollow fiber membrane was 320%.

The dialyzate side was also replaced with the inert gas. The module wasirradiated with gamma-ray (25 KGy) in the state where the membrane waswet and the inert gas was filled therein. Determination of waterpermeation performance, clearance of each solute and albuminpermeability was performed. As a result, it was demonstrated that themodule had the clearance of urea, creatinine, uric acid, phosphoric acidand VB12 of 195 ml/min, 185 ml/min, 180 ml/min, 186 ml/min and 145ml/min, respectively, and the water permeation performance of 756ml/hr/m²/mmHg, and the albumin permeability of 1.5%.

After dried, the water content in the membrane was 0%, the waterpermeation performance of the hollow fiber was 772 ml/hr/m²/mmHg, and nodegradation in performance was observed. The PVP content in the hollowfiber membrane was determined by elemental analysis and found to be3.5%. The insoluble material content in the hollow fiber afterirradiation with gamma-ray was determined and found to be 7.2%. When theforced elution test was performed to determine the concentration of PVPtransferred from the hollow fiber membrane into the aqueous layer, nopeak was detected and therefore PVP was not detected.

Example 2

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts of polysulfone(Amoco, Udel-P1700), 3 parts of polyvinyl pyrrolidone (ISP, K30) and 3parts of polyvinyl pyrrolidone (ISP, K90) were dissolved in 77 parts ofdimethylacetamide and 1 part of water with heating, to obtain a spinningsolution for membrane formation. The viscosity of the spinning solutionwas 18 Pa·s at 50° C. A module was fabricated in the same manner as inExample 1. The water content in the hollow fiber membrane after forcingout water from the membrane was 330%. The dialyzate side was alsoreplaced with the inert gas. The module was irradiated with gamma-ray(25 KGy) in the state where the membrane was wet and the inert gas wasfilled therein. Determination of water permeation performance, clearanceof each solute and albumin permeability was performed. As a result, itwas shown that the module had the clearance of urea, creatinine, uricacid, phosphoric acid and VB12 of 193 ml/min, 182 ml/min, 178 ml/min,184 ml/min and 142 ml/min, respectively, and the water permeationperformance of 720 ml/hr/m²/mmHg, and the albumin permeability of 1.8%.After dried, the water content in the membrane was 0%, the waterpermeation performance of the hollow fiber was 734 ml/hr/m²/mmHg, and nodegradation in performance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 4.0%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 7.8%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Example 3

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts of polysulfone(Amoco, Udel-P1700), 2 parts of polyvinyl pyrrolidone (ISP, K30) and 4parts of polyvinyl pyrrolidone (ISP, K90) were dissolved in 77 parts ofdimethylacetamide and 1 part of water with heating, to obtain a spinningsolution for membrane formation. The viscosity of the spinning solutionwas 23 Pa·s at 50° C. A module was fabricated in the same manner as inExample 1.

The water content in the hollow fiber membrane after forcing out waterfrom the membrane was 400%. The dialyzate side was also replaced withthe inert gas. The module was irradiated with gamma-ray (25 KGy) in thestate where the membrane was wet and the inert gas was filled therein.Determination of water permeation performance, clearance of each soluteand albumin permeability was performed. As a result, it was shown thatthe module had the water permeation performance of 702 ml/hr/m²/mmHg,the clearance of urea, creatinine, uric acid, phosphoric acid and VB12of 191 ml/min, 180 ml/min, 175 ml/min, 181 ml/min and 140 ml/min,respectively, and the albumin permeability of 1.0%. After dried, thewater content in the membrane was 0%, the water permeation performanceof the hollow fiber was 727 ml/hr/m²/mmHg, and no degradation inperformance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 4.7%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 8.3%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Example 4

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts of polysulfone(Amoco, Udel-P1700), 1 part of polyvinyl pyrrolidone (ISP, K30) and 5parts of polyvinyl pyrrolidone (ISP, K90) were dissolved in 77 parts ofdimethylacetamide and 1 part of water with heating, to obtain a spinningsolution for membrane formation. The viscosity of the spinning solutionwas 29 Pa·s at 50° C. A module was fabricated in the same manner as inExample 1.

The water content in the hollow fiber membrane after forcing out waterfrom the membrane was 380%. The dialyzate side was also replaced withthe inert gas. The module was irradiated with gamma-ray (25 KGy) in thestate where the membrane was wet and the inert gas was filled therein.Determination of water permeation performance, clearance of each soluteand albumin permeability was performed. As a result, it was shown thatthe module had the water permeation performance of 675 ml/hr/m²/mmHg,the clearance of urea, creatinine, uric acid, phosphoric acid and VB12of 190 ml/min, 179 ml/min, 173 ml/min, 179 ml/min and 138 ml/min,respectively, and the albumin permeability of 0.9%. After dried, thewater content in the membrane was 0%, the water permeation performanceof the hollow fiber was 668 ml/hr/m²/mmHg, and no degradation inperformance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 5.1%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 8.9%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Example 5

Four parts of polysulfone (Amoco, Udel-P3500), 12 parts of polysulfone(Amoco, Udel-P1700) and 6 parts of polyvinyl pyrrolidone (ISP, K90) weredissolved in 77 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 38 Pa·s at 50° C. A module wasfabricated in the same manner as in Example 1.

The water content in the hollow fiber membrane after forcing out waterfrom the membrane was 350%. The dialyzate side was also replaced withthe inert gas. The module was irradiated with gamma-ray (25 KGy) in thestate where the membrane was wet and the inert gas was filled therein.Determination of water permeation performance, clearance of each soluteand albumin permeability was performed. As a result, it was shown thatthe module had the water permeation performance of 620 ml/hr/m²/mmHg,the clearance of urea, creatinine, uric acid, phosphoric acid and VB12of 189 ml/min, 177 ml/min, 169 ml/min, 178 ml/min and 137 ml/min,respectively, and the albumin permeability of 0.8%. After dried, thewater content in the membrane was 0%, the water permeation performanceof the hollow fiber was 656 ml/hr/m²/mmHg, and no degradation inperformance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 5.5%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 9.2%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Example 6

Sixteen parts of polysulfone (Amoco, Udel-P3500), 4 parts of polyvinylpyrrolidone (ISP, K30), and 2 parts of polyvinyl pyrrolidone (ISP, K90)were dissolved in 77 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 14.0 Pa·s at 50° C. A module wasfabricated in the same manner as in Example 1.

The water content in the hollow fiber membrane after forcing out waterfrom the membrane was 260%. The dialyzate side was also replaced withthe inert gas. The module was irradiated with gamma-ray (25 KGy) in thestate where the membrane was wet and the inert gas was filled therein.Determination of water permeation performance, clearance of each soluteand albumin permeability was performed. As a result, it was shown thatthe module had the water permeation performance of 330 ml/hr/m²/mmHg,the clearance of urea, creatinine, uric acid, phosphoric acid and VB12of 195 ml/mm, 185 ml/mm, 180 ml/mm, 187 ml/min and 145 ml/min,respectively, and the albumin permeability of 0.5%. After dried, thewater content in the membrane was 0%, the water permeation performanceof the hollow fiber was 360 ml/hr/m²/mmHg, and no degradation inperformance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 3.1%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 7.5%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Comparative Example 1

Eighteen parts of polysulfone (Amoco, Udel-P3500), 6 parts of polyvinylpyrrolidone (BASF, K30) and 3 parts of polyvinyl pyrrolidone (BASF, K90)were dissolved in 72 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 70 Pa·s at 30° C. The spinningsolution was introduced to a spinneret at 50° C., and extruded, alongwith a core solution comprising 65 parts of dimethylacetamide and 35parts of water, from the spinneret through an annular double slit tubehaving an outside diameter of 0.35 mm and an inside diameter of 0.25 mm,whereby a hollow fiber membrane was formed. The membrane was subjectedto moisture conditioning at 30° C. and a dew point of 28° C. Theconditioned membrane was passed through a dry zone which had a length of250 mm, then through a coagulation bath at 40° C. comprising 20 wt % ofdimethylacetamide and 80 wt % of water. The resulting membrane wassubjected to a washing step with water at 80° C. for 20 sec, and then amoisture conditioning step with a glycerin solution. After taking offthe glycerin solution, the resulting membrane was packaged in a modulecase, and then potted. The potted bundle was provided with opening facesat the both ends to form a dialyzing module. Thereafter, the module waswashed to remove free glycerin therefrom, filled with water, and thenirradiated with gamma-ray (25 KGy). Determination of water permeationperformance, clearance of each solute and albumin permeability wasperformed. As a result, it was demonstrated that the module had theclearance of urea, creatinine, uric acid, phosphoric acid and VB12 of194 ml/min, 185 ml/min, 176 ml/min, 183 ml/min and 135 ml/min,respectively, and the water permeation performance of 716 ml/hr/m²/mmHg,and the albumin permeability of 0.7%.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 4.5%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 8.0%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1. Next,the liquid filled in the module was removed. After drying the membranewith a drier, the determination of the water permeation performance,clearance of each solute and albumin permeability was performed again.As a result, it was demonstrated that the module had the clearance ofurea, creatinine, uric acid, phosphoric acid and VB12 of 186 ml/min, 177ml/min, 169 ml/min, 176 ml/min and 119 ml/min, respectively, the waterpermeability of 0%, the water permeation performance of 10ml/hr/m²/mmHg, and the albumin permeability of 0.1%. Thus, the membraneshowed remarkable degradation in performance after drying. When aportion of the hollow fiber before drying was taken out of the moduleand dried in the same manner as described above, similar degradation inperformance was also observed.

Comparative Example 2

Seventeen parts of polysulfone (Amoco, Udel-P3500), 5 parts of polyvinylpyrrolidone (BASF, K30) and 4 parts of polyvinyl pyrrolidone (BASF, K90)were dissolved in 73 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 40 Pa·s at 50° C. A module wasfabricated in the same manner as in Comparative Example 1. The modulewas irradiated with gamma-ray in the state where water is filled in themodule. Determination of water permeation performance, clearance of eachsolute and albumin permeability of the module was performed. As aresult, it was demonstrated that the module had the clearance of urea,creatinine, uric acid, phosphoric acid and VB12 of 195 ml/min, 186ml/min, 177 ml/min, 184 ml/min and 137 ml/min, respectively, and thewater permeation performance of 600 ml/hr/m²/mmHg, and the albuminpermeability of 1.2%.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 4.8%. The insoluble material content in thehollow fiber was determined and found to be 10.0%. When the forcedelution test was performed to determine the concentration of PVPtransferred from the hollow fiber membrane into the aqueous layer, PVPwas not detected, as in the case of Example 1. Next, the liquid filledin the module was removed. After drying the membrane with a drier, thedetermination of the water permeation performance, clearance of eachsolute and albumin permeability was performed again. As a result, it wasdemonstrated that the module had the clearance of urea, creatinine, uricacid, phosphoric acid and VB12 of 189 ml/min, 179 ml/min, 172 ml/min,178 ml/min and 126 ml/min, respectively, the water permeability of 0%,the water permeation performance of 200 ml/hr/m²/mmHg, and the albuminpermeability of 0.2%. Thus, the membrane showed remarkable degradationin performance after drying. When a portion of the hollow fiber beforedrying was taken out of the module and dried in the same manner asdescribed above, similar degradation in performance was also observed.

Comparative Example 3

Seventeen parts of polysulfone (Amoco, Udel-P3500), 5 parts of polyvinylpyrrolidone (BASF, K30) and 3 parts of polyvinyl pyrrolidone (BASF, K90)were dissolved in 74 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 33 Pa·s at 50° C. A module wasfabricated in the same manner as in Comparative Example 1. The modulewas irradiated with gamma-ray in the state where water is filled in themodule. Determination of water permeation performance, clearance of eachsolute and albumin permeability was performed. As a result, it wasdemonstrated that the module had the clearance of urea, creatinine, uricacid, phosphoric acid and VB12 of 196 ml/min, 187 ml/min, 178 ml/min,185 ml/min and 138 ml/min, respectively, and the water permeationperformance of 525 ml/hr/m²/mmHg, and the albumin permeability of 0.8%.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 4.0%. The insoluble material content in thehollow fiber was determined and found to be 9.3%. When the forcedelution test was performed to determine the concentration of PVPtransferred from the hollow fiber membrane into the aqueous layer, PVPwas not detected, as in the case of Example 1. Next, the liquid filledin the module was removed. After drying the membrane with a drier, thedetermination of the water permeation performance, clearance of eachsolute and albumin permeability was performed again. As a result, it wasdemonstrated that the module had the clearance of urea, creatinine, uricacid, phosphoric acid and VB12 of 191 ml/min, 181 ml/min, 173 ml/min,180 ml/min and 126 ml/min, respectively, the water permeability of 0%,the water permeation performance of 340 ml/hr/m²/mmHg, and the albuminpermeability of 0.5%. Thus, the membrane showed remarkable degradationin performance after drying. When a portion of the hollow fiber beforedrying was taken out of the module and dried in the same manner asdescribed above, similar degradation in performance was also observed.

Comparative Example 4

Sixteen parts of polysulfone (Amoco, Udel-P3500), 4 parts of polyvinylpyrrolidone (ISP, K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90)were dissolved in 77 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 14.0 Pa·s at 50° C. A module wasfabricated in the same manner as in Example 1, except that the dry zonewas not dry mist atmosphere.

The water content in the hollow fiber membrane after forcing out waterfrom the membrane was 230%. The dialyzate side was also replaced withthe inert gas. The membrane was irradiated with gamma-ray (25 KGy) inthe state where the membrane was wet and the inert gas was filledtherein. Determination of water permeation performance, clearance ofeach solute and albumin permeability was performed. As a result, it wasshown that the module had the water permeation performance of 350ml/hr/m²/mmHg, the clearance of urea, creatinine, uric acid, phosphoricacid and VB12 of 190 ml/min, 180 ml/min, 175 ml/min, 182 ml/min and 138ml/min, respectively, and the albumin permeability of 0.6%. After dried,the water content in the membrane was 0%, the water permeationperformance of the hollow fiber was 340 ml/hr/m²/mmHg, and nodegradation in performance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 3.3%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 7.8%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, PVP was not detected, as in the case of Example 1.

Comparative Example 5

Sixteen parts of polysulfone (Amoco, Udel-P3500), 4 parts of polyvinylpyrrolidone (ISP, K30) and 2 parts of polyvinyl pyrrolidone (ISP, K90)were dissolved in 77 parts of dimethylacetamide and 1 part of water withheating, to obtain a spinning solution for membrane formation. Theviscosity of the spinning solution was 14.0 Pa·s at 50° C. A module wasfabricated in the same manner as in Example 1, except that the waterfilled in the membrane was forced out with compressed air and theatmosphere was not replaced with any inert gas. The water content in thehollow fiber membrane in this state was 260%. The membrane wasirradiated with gamma-ray (25 KGy) in the state where air was filledtherein and the membrane was wet. Determination of water permeationperformance, clearance of each solute and albumin permeability wasperformed. As a result, it was shown that the module had the waterpermeation performance of 350 ml/hr/m²/mmHg, the clearance of urea,creatinine, uric acid, phosphoric acid and VB12 of 195 ml/min, 185ml/min, 180 ml/min, 187 ml/min and 145 ml/min, respectively, and thealbumin permeability of 0.5%. After dried, the water content in themembrane was 0%, the water permeation performance of the hollow fiberwas 340 ml/hr/m²/mmHg, and no degradation in performance was observed.

The PVP content in the hollow fiber membrane was determined by elementalanalysis and found to be 3.1%. The insoluble material content in thehollow fiber after irradiation with gamma-ray was determined and foundto be 7.8%. When the forced elution test was performed to determine theconcentration of PVP transferred from the hollow fiber membrane into theaqueous layer, however, 1255 ppm of PVP was detected in the aqueouslayer.

According to the present invention, a dialyzer for blood treatment whichhas incorporated therein a dry-type semepermeable membrane havingadvantages such as light-weight and free from the problem of freeze,wherein the semipermeable membrane has good water permeability anddialyze performance; a dialyzer for blood treatment which islight-weight, easy to handle, and exhibits a reduced elution of ahydrophilic polymer; and a process for producing a semipermeablemembrane for blood treatment suitable for the dialyzers.

TABLE 1 Examples Comparative Examples 1 2 3 4 5 6 1 2 3 4 5 Waterpermeation 772/756 734/720 727/702 668/675 656/620 360/330 10/716200/600 340/525 350/340 350/340 performance ca. 1/3 ca. 2/3after-dry/before-dry PSF/PVP (K30/K90) 16(4/2) 16/(3/3) 15/(2/4)16/(1/5) 16/(0/6) 16/(4/2) 18/(6/3) 17/(5/4) 17/(5/3) 16/(4/2) 16/(4/2)Dry zone Dry mist No mist Dry mist Filled gas N₂ Air Liquid content at320 330 400 380 350 260 >1000 >1000 >1000 230 260 γ-ray irradiation (%)PVP content (%) 3.5 4.0 4.7 5.1 5.5 3.1 4.5 4.8 4.0 3.3 3.1 Albuminpermeability (%) 1.5 1.8 1.0 0.9 0.8 0.5 0.1 0.2 0.5 0.6 0.5 Urea(pre/post) ml/min 195 193 191 190 189 195 194/188 195/189 196/191 190195 Cr (pre/post) 185 182 180 179 177 185 185/177 186/179 187/181 180185 Ureic acid (pre/post) 180 178 175 173 169 180 176/169 177/172178/173 175 180 Phosphoric acid (pre/post) 186 184 181 179 178 187183/176 184/178 185/180 182 187 Vitamin (pre/post) 145 142 140 138 137145 135/119 137/126 138/126 138 145 PVP elution (PPM) 0 0 0 0 0 0 0 0 00 1255 Insoluble substances (%) 7.2 7.8 8.3 8.9 9.2 7.5 8.0 10.0 9.3 7.87.8

1. A process for producing a dialyzer having incorporated therein asemipermeable membrane which comprises a hydrophobic polymer and ahydrophilic polymer, the process comprising: drying the semipermeablemembrane; and saturating the dried semipermeable membrane with water ata water ratio of not smaller than 100% and not higher than 1000% basedon the dry weight of the semipermeable membrane, providing an inert gasatmosphere to the inside of the dialyzer, and then irradiating thesemipermeable membrane with gamma-ray in the inert gas atmosphere. 2.The process according to claim 1, wherein the water ratio is not smallerthan 100% and not higher than 600% based on the dry weight ofsemipermeable membrane.
 3. The process according to claim 1, wherein theinert gas is nitrogen or carbon dioxide gas.
 4. The process according toclaim 1, wherein the step of drying is performed for reducing the watercontent in the semipermeable membrane to a level not higher than 5%. 5.The process according to claim 4, wherein the water content is nothigher than 2%.
 6. The process according to claim 1, wherein thesemipermeable membrane is a hollow fiber membrane, wherein the hollowfiber membrane is produced by dry-wet spinning from a spinning solutioncomprising 15 to 18% by weight of a hydrophobic polymer and 4 to 8% byweight of a hydrophilic polymer, and wherein the dry zone being filledwith dry mist.
 7. The process according to claim 6, wherein thehydrophobic polymer is a polysulfonic resin and the hydrophilic polymeris polyvinyl pyrrolidone.